Clinical and genetic characterization of 47 Chinese pediatric patients with Pitt-Hopkins syndrome: a retrospective study.

BACKGROUND: Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder that remains underdiagnosed and its clinical presentations and mutation profiles in a diverse population are yet to be evaluated. This retrospective study aims to investigate the clinical and genetic characteristics of Chinese patients with PTHS. METHODS: The clinical, biochemical, genetic, therapeutic, and follow-up data of 47 pediatric patients diagnosed with PTHS between 2018 and 2021 were retrospectively analyzed. RESULTS: The Chinese PTHS patients presented with specific facial features and exhibited global developmental delay of wide severity range. The locus heterogeneity of the TCF4 gene in the patients was highlighted, emphasizing the significance of genetic studies for accurate diagnosis, albeit no significant correlations between genotype and phenotype were observed in this cohort. The study also reports the outcomes of patients who underwent therapeutic interventions, such as ketogenic diets and biomedical interventions. CONCLUSIONS: The findings of this retrospective analysis expand the phenotypic and molecular spectra of PTHS patients. The study underscores the need for a long-term prospective follow-up study to assess potential therapeutic interventions.

diseaseGPS: auxiliary diagnostic system for genetic disorders based on genotype and phenotype.

SUMMARY: The next-generation sequencing brought opportunities for the diagnosis of genetic disorders due to its high-throughput capabilities. However, the majority of existing methods were limited to only sequencing candidate variants, and the process of linking these variants to a diagnosis of genetic disorders still required medical professionals to consult databases. Therefore, we introduce diseaseGPS, an integrated platform for the diagnosis of genetic disorders that combines both phenotype and genotype data for analysis. It offers not only a user-friendly GUI web application for those without a programming background but also scripts that can be executed in batch mode for bioinformatics professionals. The genetic and phenotypic data are integrated using the ACMG-Bayes method and a novel phenotypic similarity method, to prioritize the results of genetic disorders. diseaseGPS was evaluated on 6085 cases from Deciphering Developmental Disorders project and 187 cases from Shanghai Children's hospital. The results demonstrated that diseaseGPS performed better than other commonly used methods. AVAILABILITY AND IMPLEMENTATION: diseaseGPS is available to freely accessed at https://diseasegps.sjtu.edu.cn with source code at https://github.com/BioHuangDY/diseaseGPS.

Effect of Manufactured Sand with Different Quality on Chloride Penetration Resistance of High-Strength Recycled Concrete.

High-strength manufactured sand recycled aggregate concrete (MSRAC) prepared with manufactured sand (MS) and recycled coarse aggregate (RCA) is an effective way to reduce the consumption of natural aggregate resources and environmental impact of concrete industry. In this study, high-, medium- and low-quality MS, which were commercial MS local to Changzhou and 100% by volume of recycled coarse aggregate, were used to prepare MSRAC. The quality of MS was determined based on stone powder content, methylene blue value (MBV), crushing value and soundness as quality characteristic parameters. The variation laws of compressive strength and chloride penetration resistance of high-strength MSRAC with different rates of replacement and different qualities of MS were explored. The results showed that for medium- and low-quality MS, the compressive strength of the MSRAC increased first and then decreased with increasing rate of replacement. Conversely, for high-quality MS, the compressive strength gradually increased with increasing rate of replacement. The chloride diffusion coefficient of MSRAC increased with decreasing MS quality and increasing rate of replacement. The chloride diffusion coefficient of MSRAC basically met the specifications for 50-year and 100-year design working life when the chloride environmental action was D and E. To prepare high-strength MSRAC, high-quality MS can 100% replace RS (river sand), while rates of replacement of 50-75% for medium-quality MS or 25-50% for low-quality MS are proposed. Scanning Electron Microscope (SEM) images indicated that an appropriate amount of stone powder is able to improve the compressive strength of RAC, but excessive stone powder content and MBV are unfavorable to the compressive strength and chloride penetration resistance of RAC.

Generation and characterization of an iPSC line (SHCMDLi001-A) from a 12-year-old Chinese Han patient with TRAF7 syndrome and of an iPSC line (SHCMDLi002-A) from a control individual.

Mutations in TRAF7 cause developmental delay and cardiac, facial, digital anomalies. c.1964G > A variant was most recurrent, suggesting its essentiality of pathogenicity. Further studies to determine the underlying mechanism of c.1964G > A variant are warranted. But no patient-specific cellular models have been generated. Here, we generated an iPSC line with c.1964G > A variant (SHCMDLi001-A) and a line from healthy individual (SHCMDLi002-A). Characterization of SHCMDLi001-A and SHCMDLi002-A demonstrated these iPSCs are free of exogenous reprogramming genes, expressed pluripotency markers, exhibited a normal karyotype and were potential of three germ layer differentiation. These lines provide a valuable resource for studying disease-causing mechanism of TRAF7 variant.

Pitt-Hopkins syndrome: phenotypic and genotypic description of four unrelated patients and structural analysis of corresponding missense mutations.

Pitt-Hopkins syndrome is an underdiagnosed neurodevelopmental disorder which is characterized by specific facial features, early-onset developmental delay, and moderate to severe intellectual disability. The genetic cause, a deficiency of the TCF4 gene, has been established; however, the underlying pathological mechanisms of this disease are still unclear. Herein, we report four unrelated children with different de novo mutations (T606A, K607E, R578C, and V617I) located at highly conserved sites and with clinical phenotypes which present variable degrees of developmental delay and intellectual disability. Three of these four missense mutations have not yet been reported. The patient with V617I mutation exhibits mild intellectual disability and has attained more advanced motor and verbal skills, which is significantly different from other cases reported to date. Molecular dynamics simulations are used to explore the atomic level mechanism of how missense mutations impair the functions of TCF4. Mutations T606A, K607E, and R578C are found to affect DNA binding directly or indirectly, while V617I only induces subtle conformational changes, which is consistent with the milder clinical phenotype of the corresponding patient. The study expands the mutation spectrum and phenotypic characteristics of Pitt-Hopkins syndrome, and reinforces the genotype-phenotype correlation and strengthens the understanding of phenotype variability, which is helpful for further investigation of pathogenetic mechanisms and improved genetic counseling.

A de novo MAPRE2 variant in a patient with congenital symmetric circumferential skin creases type 2.

BACKGROUND: Congenital symmetric circumferential skin creases (CSCSC) was initially described five decades ago. Exome sequencing has recently revealed the genetic etiology of CSCSC. Pathogenic variants in TUBB (OMIM# 191130) and MAPRE2 (OMIM# 605789) have been linked to CSCSC1 (OMIM# 156610) and CSCSC2 (OMIM# 616734), respectively, in an autosomal dominant manner. Four pathogenic variants in MAPRE2 have been previously reported to be associated with CSCSC2. METHODS: Whole-exome sequencing (WES) has been performed and an in-house pipeline was used to conduct a phenotype-driven data analysis. All candidate variants were confirmed by Sanger sequencing. RESULTS: Here we report a 2-year-old boy characterized by absent expressive speech, normal to mild over growth, facial dysmorphic features, remarkable circumferential skin creases on both forearms and ankles. WES disclosed a de novo missense MAPRE2 variant, c.518G>A (p.Arg173Gln), as the molecular cause of this complex phenotype. We described detailed clinical characterization of this patient and compared the available clinical data of individuals with MAPRE2 variants to demonstrate the phenotypic spectrum. CONCLUSION: Our study reports the first patient of Asian origin with CSCSC2 due to a pathogenic mutation of MAPRE2 and expands the clinical and genetic spectrum of CSCSC2.

Expression characteristic and significance of interleukin-6, nuclear factor kappa beta, and bone formation markers in rat models of osteoporosis.

The goal of this study was to investigate the expression levels of interleukin 6 (IL-6), nuclear factor kappa beta (NF-kappabeta), bone-specific alkaline phosphatase (BALP), and bone osteocalcin (BGP) in rats with osteoporosis and their significance in the pathogenesis of osteoporosis. In all, 60 adult female SD rats were divided randomly into 3 groups of 20 rats each: normal control group (control), sham-operated group (sham), and ovariectomized group (OVX). In 2, 3, 4, 5, and 6 months after surgery, 4 rats were randomized from each group for assays of BMD, IL-6, BALP, and BGP. Then, the rats were sacrificed for the detection of IL-6 and NF-kappabeta expression levels in bone tissue by quantitative real-time RT-PCR analysis. Compared with the sham (0.097 +/- 0.04 g/cm2, 0.097 +/- 0.01 g/cm2, 0.095 +/- 0.07 g/cm2) and control group (0.107 +/- 0.01 g/cm2, 0.103 +/- 0.07 g/cm2, 0.108 +/- 0.06 g/cm2), the BMD of rats in the OVX group was reduced remarkably in 4, 5, and 6 months (0.082 +/- 0.05 g/cm2, 0.073 +/- 0.02 g/cm2, 0.061 +/- 0.05 g/cm2, respectively; P < 0.01); the serum IL-6 level increased significantly from 2 to 6 months after surgery (P < 0.01); and the serum levels of BALP and BGP were greater at 4, 5, and 6 months (P < 0.05). The quantitative real-time RT-PCR analysis demonstrated that IL-6 and NF-kappabeta mRNA levels in OVX group increased in a time-dependent manner. Moreover, the IL-6, NF-kappabeta, BALP, and BGP levels were correlated negatively with the BMD. Meanwhile, a positive correlation was observed between IL-6 and NF-kappabeta. In conclusion, the expression levels of IL-6, NF-kappabeta, and bone formation markers may increase significantly in the osteoporosis rats. These molecules could play a role in the pathogenesis.